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Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation

A Correction to this article was published on 20 December 2021

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Abstract

Metastatic recurrence is still a major challenge in breast cancer treatment, but the underlying mechanisms remain unclear. Here, we report that a small adaptor protein, SH3BGRL, is upregulated in the majority of breast cancer patients, especially elevated in those with metastatic relapse, indicating it as a marker for the poor prognosis of breast cancer. Physiologically, SH3BGRL can multifunctionally promote breast cancer cell tumorigenicity, migration, invasiveness, and efficient lung colonization in nude mice. Mechanistically, SH3BGRL downregulates the acting-binding protein profilin 1 (PFN1) by accelerating the translation of the PFN1 E3 ligase, STUB1 via SH3BGRL interaction with ribosomal proteins, or/and enhancing the interaction of PFN1 with STUB1 to accelerate PFN1 degradation. Loss of PFN1 consequently contributes to downstream multiple activations of AKT, NF-kB, and WNT signaling pathways. In contrast, the forced expression of compensatory PFN1 in SH3BGRL-high cells efficiently neutralizes SH3BGRL-induced metastasis and tumorigenesis with PTEN upregulation and PI3K-AKT signaling inactivation. Clinical analysis validates that SH3BGRL expression is negatively correlated with PFN1 and PTEN levels, but positively to the activations of AKT, NF-kB, and WNT signaling pathways in breast patient tissues. Our results thus suggest that SH3BGRL is a valuable prognostic factor and a potential therapeutic target for preventing breast cancer progression and metastasis.

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Fig. 1: SH3BGRL is upregulated in breast cancers with metastasis.
Fig. 2: SH3BGRL enhances breast cancer tumorigenicity and metastasis.
Fig. 3: SH3BGRL interacts and downregulates PFN1 in breast cancers.
Fig. 4: SH3BGRL downregulates PFN1 by ubiquitination degradation of PFN1 through STUB1 translational regulation or interaction of PFN1 and STUB1.
Fig. 5: SH3BGRL-PFN1 axis activates AKT, NF-kB and WNT signaling.
Fig. 6: PFN1 is a bridge for SH3BGRL-mediated breast cancer metastasis and tumorigenesis.
Fig. 7: Relevance of SH3BGRL-PFN1 axis with downstream AKT, NF-kB, and WNT signalings in breast cancer.

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Funding

This work was supported by National Science Foundation of China (No. 81672704), the Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translation Research of Hakka Population (2018B030322003KF02), and Natural Science Foundation of Guangdong Province (No. 2021A1515010999) to WH.

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Contributions

S Zhang, S Yang, and H Wang conceived the research and designed the experiments, S Zhang performed the most experiments and data analyses; X Guo collect samples and performed IHC staining with analysis, X Liu performed colony formation assay, XZ Zhong performed Immunoblots of genes in breast cancer tissues; S Zhang, H Wang and S Yang wrote the draft. All authors approved the final manuscript submission.

Corresponding authors

Correspondence to Shulan Yang or Haihe Wang.

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Competing interests

Drs. Haihe Wang and Shulan Yang, researchers on the study team, are co-inventors on Patent 201710512823.6 (Sun Yat-sen University) which deals with the application of SH3BGRL as a diagnostic and therapy target. No other authors have competing interests.

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Zhang, S., Guo, X., Liu, X. et al. Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation. Oncogene 40, 5677–5690 (2021). https://doi.org/10.1038/s41388-021-01970-8

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